1. Field of the Invention
This invention provides novel processes for preparing substituted pyrrolizine compounds. More particularly, this invention provides processes for the preparation of 5-aroyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylates (I) ##STR2## from 2-aroylpyrroles. Hydrolysis and mono-decarboxylation of compounds of formula I affords ketorolac and related compounds.
2. Background to the Invention
5-Aroyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acids (II), and the pharmacologically acceptable salts and esters thereof, are now under study ##STR3## as analgesic, anti-inflammatory, and anti-pyretic agents for mammals, including man. They are also smooth muscle relaxants.
Two exemplary compounds under clinical study in man are ketorolac, 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, (II, Ar=C.sub.6 H.sub.5) which is currently being marketed in the U.S., Italy, Holland, and New Zealand, and anirolac, 5-p-anisoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, (II, Ar=p-CH.sub.3 O-C.sub.6 H.sub.5), both disclosed in U.S. Pat. No. 4,089,969 (Muchowski et al., assigned to Syntex (U.S.A.) Inc.). Other compounds, where the 5-aroyl substituents are substituted or unsubstituted benzoyl, furoyl, thenoyl, and pyrroyl, and where the 6-and/or 7-position on the pyrrolizine nucleus is optionally substituted by lower alkyl or halogen, and uses thereof, are also disclosed in a series of patents assigned to Syntex (U.S.A.) Inc., beginning with U.S. Pat. No. 4,089,969, and including U.S. Pat. Nos. 4,087,539; 4,097,579; 4,140,698; 4,232,038; 4,344,943; 4,347,186; 4,458,081; 4,347,187; 4,454,326; 4,347,185; 4,505,927; 4,456,759; 4,353,829; 4,397,862; 4,457,941; and 4,454,151. U.S. Pat. Nos. 4,511,724 and 4,536,512, assigned to Merck & Co., Inc., disclose 5-(substituted pyrrol-2-oyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid derivatives and 5-(2,3-dihydro-1H-pyrrolizine-2-oyl)-2,3-dihydro-1H-pyrrolizine-1-carboxyl ic acid derivatives, respectively.
Various methods for the preparation of these pyrrolizines are exemplified in the patent and chemical literature.
For example, U.S. Pat. Nos. 4,347,186; 4,458,081; 4,347,187; and 4,454,326 disclose the preparation of 5-aroyl-pyrrolizines from pyrroles, and certain intermediates, by the following route: ##STR4## wherein: R.sup.1 and X are independently hydrogen or lower alkyl; and
Ar is a moiety selected from the group consisting of ##STR5## in which: R.sup.2 is hydrogen, methyl, chloro, or bromo, the R.sup.2 substitution being at the 3-, 4- or 5-position of the ring; PA1 R.sup.3 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyl, fluoro, chloro or bromo, the R3 substitution being at any available position in the ring; PA1 R.sup.4 is hydrogen or lower alkyl; and PA1 Y is oxygen or sulfur. PA1 U.S. Pat. Nos. 4,347,185; 4,505,927; and 4,456,759 disclose the preparation of 5-aroyl-pyrrolizines from pyrroles, and certain intermediates, by the following route: ##STR6## wherein: R.sup.5 is hydrogen or lower alkyl; PA1 R.sup.6 is lower alkyl: PA1 X is hydrogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxyl, lower alkylcarbonyl, sulfonic acid, sulfonic acid alkyl ester, fluoro, chloro, or bromo; and PA1 Y is chloro or bromo. PA1 U.S. Pat. No. 4,873,340, issued Oct. 10, 1989, discloses the preparation of 5-aroyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylates from 2-halopyrroles, and certain intermediates, by the following route: ##STR7## wherein R.sup.8 is lower alkyl; PA1 Ar is an aryl group not containing hydrogen bonded to a pyrrole nitrogen; and PA1 each R.sup.7 is independently lower alkyl; and PA1 X is bromo or chloro. PA1 Ar is an aryl group, which does not contain nitrogen which is substituted with hydrogen; from 2-aroylpyrroles via radical addition followed by an intermolecular double alkylation. PA1 X is selected from the group consisting of alkoxycarbonyl, acyloxy, and hydrogen.
It has recently been reported that iron (III) salts and manganese (III) acetate can induce the oxidative radical cyclization of .beta.-dicarbonyl moieties to form homocyclic aromatic systems. A. Citterio, et al., Tetrahedron Letters, 30, 1289 (1989); J. Org. Chem., 54, 2713 (1989).
The disclosures of these patents and literature articles and other patents and articles referred to throughout this application are incorporated herein by reference.